Aberrant expression of β-dystroglycan may be due to processing by matrix metalloproteinases-2 and -9 in oral squamous cell carcinoma
Introduction
It is well known that cell–cell and cell–extracellular matrix (ECM) interactions have a pivotal function in the development and maintenance of normal cell architecture. Abnormalities of the interactions between tumour cells and ECM proteins are thought to be common features of malignant tumors and crucial step for initiation of tumor metastasis.1 During the cell–cell and/or cell–ECM interactions, cell adhesion molecules are thought to play many important roles, including attachment of epithelial cell to the basal lamina, information exchange, cytoskeleton organization, and signal transduction. However, studies on cell–ECM interactions have largely focused on the integrins, an extensively characterized family of heterodimeric receptors.1, 2 In recent years, the role of non-integrin receptors has gained much attention in cancer biology.
Dystroglycan (DG) is a non-integrin adhesion molecule expressed by a variety of tissues, interacting with extracellular proteins including laminin, perlecan and agrin, and membrane proteins such as the neurexins. DG is a product of a single gene (DAG1), but the primary peptide is post-translationally cleaved into two protein subunits (α and β), which interact to form a functional non-covalent complex.3 DG was firstly isolated from skeletal muscle, and has been mainly studied for its role in skeletal muscle cell stability and its alterations in muscular diseases, such as dystrophies. In recent years, however, DG has been reported to play important roles in regulating basal membrane morphogenesis, cytoskeletal organization, cell polarization, cell growth, signal transduction, maintenance of tissue integrity in epithelial cells.4, 5, 6 These findings might implicate DG in cancer biology. In fact, abnormalities in DG expression in human breast, colon, prostate, and oral cancers have been described.7, 8, 9, 10 These studies confirmed that DG expression was reduced or lost in primary and metastatic cancers with no rearrangement of DG mRNA. However, the role of β-DG degradation and its mechanisms were poorly understood.
It is well known that matrix metalloproteinases (MMPs) are an important group of proteolytic enzymes that are capable of degrading the basement membrane, as well as certain cell membrane proteins. MMPs are produced by cancer cells or through the induction of surrounding stromal cells, and play crucial roles in the degradation and remodeling of ECM and tumour angiogenesis.11 Recently, Yamada et al. found that the processing of β-DG by MMP could cause the disruption of the link between ECM and cell membrane via the dystroglycan complex in muscle cells.12 This provides a possible mechanism underlying the degradation of β-DG in cancer.
Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide and often invades tissues locally and metastasises to cervical lymph nodes. The purpose of this study was to investigate the expression of α-, β-DG in OSCC, the implications of aberrant β-DG in the migration and invasion of cancer cells, and the possible role of MMPs in the proteolytic processing of β-DG in OSCC.
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Antibodies and reagents
Mouse monoclonal anti-human beta-DG antibody (clone 43DAG/8D5) was purchased from Novocastra Laboratories Ltd., Newcastle, UK. Two mouse anti-α-DG monoclonal antibodies were used: VIA4-1 (Upstate Lab, USA) and anti-α-DG (IgM, US Biological, USA). Mouse monoclonal anti-human MMP-2 (8B4) and MMP-9 (2C3) antibodies were purchased from Santa Cruz Biotechnology Inc., Santa Cruz, CA, USA. 1,10-Orthophenanthroline monohydrate (Sigma–Aldrich, Poole, UK) was used as matrix metalloprotease (MMP)
Abnormal expression of α, β-DG in oral cancer
In normal oral epithelium, both α- and β-DG were found to localize in the basal cell layers of the squamous epithelium, in muscle sarcolemma and connective tissue blood vessels (Fig. 1A and B). The DG expression was completely altered in OSCC. A nearly total lack of α-DG staining was found in all OSCC samples (Fig. 1C and D). Unlike the specific expression pattern in normal epithelium, however, the β-DG staining in cancer tissue was highly variable. The β-DG expression was frequently reduced or
Discussion
Dystroglycan is a cellular receptor expressed by a variety of tissues, interacting with extracellular proteins including laminin, perlecan and agrin, and membrane proteins such as the neurexins.3, 13 Specific changes in DG expression have been described in human breast, colon, prostate and head and neck cancers.7, 8, 9, 10 However to our knowledge, there are no studies that have investigated the aberrant expression of DG and the possible mechanisms underlying the degradation of β-DG in oral
Conflict of Interest Statement
None declared.
Acknowledgements
This work was supported by the Grant from Royal College of Surgeons of England awarded to Professor P.A. Brennan, and the Grant from National Natural Science Foundation of China (No. 30772435) awarded to Dr. Zheng-Jun Shang. The authors also thank Dr. Chu Fu Lien for his kind help in the experiment.
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Loss of LARGE2 disrupts functional glycosylation of α-dystroglycan in prostate cancer
2013, Journal of Biological ChemistryCitation Excerpt :In a variety of adenocarcinomas, including prostate, expression of DG protein, αDG and/or βDG, is reduced and this is associated with increased tumor aggressiveness and loss of extracellular matrix integrity, e.g. (38, 39). So far, all evidence points toward post-transcriptional mechanisms, including proteolysis and hypoglycosylation to account for the observed loss of DG expression in cancer (35, 39–42). Herein we describe a novel mechanism accounting for the loss of functional αDG glycosylation in prostate cancer cell lines and prostate cancer specimens, reduced expression of LARGE2, a protein not previously implicated in cancer.
MMP-mediated cleavage of β-dystroglycan in myelin sheath is involved in autoimmune neuritis
2010, Biochemical and Biophysical Research CommunicationsCitation Excerpt :Therefore, DG complex plays a unique role in myelin formation and stability, and its absence may cause the dysmyelination in peripheral nerve system (PNS) [8–11]. The proteolysis of β-DG has been observed under various pathological conditions [12–18], in which matrix metalloproteases (MMP) disrupt DG complex by cleaving the extracellular domain of β-DG into β-DG30 in the peripheral tissues [17] as well as on astrocyte end-feet in experimental autoimmune encephalomyelitis [18]. β-DG was selectively cleaved by MMP-2 and MMP-9 [19–21].
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